This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The ubiquitous beta-herpes virus CMV exhibits a number of natural adaptations, including 1) elicitation and long-term maintenance of uniquely strong (mucosally-oriented) cellular and humoral immunity, 2) lifelong persistence despite this robust immune response, 3) the ability to subclinically re-infect and immunologically boost fully immune hosts, and 4) little pathogenicity in normal hosts that make it a provocative candidate for development as a vaccine vector for chronic, elusive lentiviral pathogens like HIV/SIV (for which protection will likely require potent, long-lasting cellular and humoral immunity). The overall goal of this proposal is to use the rhesus macaque (RM) model (RhCMV/SIV) to explore the hypothesis that the special adaptations of CMV vectors (immunogenicity, persistence, ability to re-infect immune hosts) can quantitatively and/or qualitatively improve on the immunogenicity of current vaccine strategies, and as a result, safely elicit protective lentivirus-specific immunity. This project supported construction of RhCMV/SIV vectors, their initial in vitro and in vivo testing, and finally assessment of their efficacy in protection against mucosal administered, highly pathogenic SIV. These vectors elicit high frequency, effector memory-biased T cell responses that are able to control SIV infection in the first hours to days after mucosal inoculation, and effectively prevent systemic, progressive infection.